Human RIG-I deficiency confers susceptibility to Kaposi Sarcoma via loss of latency control
Kaposi sarcoma (KS), caused by the DNA-virus Kaposis sarcoma-associated herpesvirus (KSHV), occurs during T cell immunosuppression (HIV, transplant) or sporadically in some immunocompetent and aging individuals (endemic, classic KS respectively). In absence of known T cell immunosuppression KS pathogenesis remains enigmatic. KS therapy with topical or oral retinoid medication, or recombinant alpha interferon, can induce remission and suggests the involvement of two signalling pathways. Retinoic acid-inducible gene-I (RIG-I) encoded by DDX58 is canonically a sensor of RNA-viruses, its function in human immunity against DNA-viruses remains poorly defined. We report a patient with classic KS, carrying a homozygous nonsense (p.Q393*) mutation in DDX58, abolishing RIG-I expression and specifically impairing RIG-I agonist responses. In isogenic cell models, loss of RIG-I compromised responses during both KSHV primary infection and viral reactivation, diminishing induction of type I interferons and interferon-stimulated genes, skewing to a persistent latent viral gene program, and dysregulating cellular pro-oncogenic pathways by transcriptomic and proteomic profiling. This work defines the first innate immunodeficiency underlying classical KS, revealing RIG-Is role in KSHV immunopathogenesis and expanding its function in human antiviral immunity beyond RNA-viruses, while identifying promising therapeutic targets. Significance statementRIG-I deficiency causes classic KS by failing to control KSHV infection and reactivation, expanding its role beyond RNA-viruses.